Erythropoietin, a hypoxia-inducible cytokine, is required for survival, proliferation and differentiation of erythroid progenitor cells and erythropoietin receptor null mice die in utero due to lack of mature erythrocyte production. Nonetheless, erythropoietin and its receptor are expressed in the nervous system during development and adulthood. We have shown that erythropoietin receptor is expressed at high levels in embryonic brain and specifically on neuronal cells, and that erythropoietin can stimulate neural cell formation and prevent apoptosis during development. In erythropoietin receptor-null mice, the number of neural progenitor cells is decreased. Erythropoietin receptor-null neurons are more sensitive to hypoxia and do not survive after exposure to hypoxia. We find that neural stem cells express erythropoietin receptor and that endogenous erythropoietin regulates neural stem cell proliferation and facilitates learning/memory. This was demonstrated by developing conditional knockout mice with selective erythropoietin receptor expression in hematopoietic tissue but not in brain. These mice have normal hematopoiesis and erythrocyte production and survive to adulthood. However, neural stem cell proliferation in adult brain is reduced as is learning/memory. These observations demonstrate that erythropoietin is neuroprotective independent of insult, injury or ischemic events, and functions beyond stimulation of erythropoiesis contributing to oxygen delivery to the brain. Erythropoietin can also stimulate proliferation and angiogenesis of endothelial cells that express erythropoietin receptors. We found that erythropoietin receptor is inducible by erythropoietin in primary human endothelial cells of vein and artery and cells from a human bone marrow microvascular endothelial line to a much greater extent at low oxygen tension than in room air. In response to erythropoietin found an increase in endothelial nitric oxide synthase that produces NO to maintain blood pressure homeostasis and blood flow. Erythropoietin also produced a corresponding increase in NO during hypoxia. NO activates soluble guanosine cyclase to produce cyclic guanosine monophosphate which was also increased by erythropoietin. These results suggest that low oxygen tension increases endothelial cell capacity to produce NO in response to erythropoietin by induction of both erythropoietin receptor and eNOS. This effect of erythropoietin may be a physiologically relevant mechanism to counterbalance the hypertensive effects of increased hemoglobin-related NO destruction resulting from hypoxia-induced increased red cell mass.